1. Field of the Invention
The invention relates to phenolic acid amides of hydroxy-substituted bezylamines, to a process for their preparation and to their use as antioxidants or free-radical scavengers, in particular in cosmetic and pharmaceutical preparations and foods, and for the protection of cells and tissue of mammals against the damaging effect of free radicals and reactive oxygen species which accelerate aging. The invention also relates to cosmetic and pharmaceutical preparations comprising these phenolic acid amides.
2. Discussion of the Background
The autoxidation of lipids, proteins, DNA and other biomolecules is one of the main factors responsible for the aging of physiological systems, including human skin (cf. for example B. Halliwell, M. A. Murcia, S. Chirico, O. I. Aruoma, Critical Reviews in Food Science and Nutrition, 1995, 35 (1&2), 7-20 and literature cited therein). It is assumed that the damage of biomolecules and cells by oxidative stress leads to many diseases (cf. M. J. Thomas, Critical Reviews in Food Science and Nutrition, 1995, 35 (1&2), 21-39). This is almost certainly the case for some types of cancer. However, also in the case of arthritis and arteriosclerosis a direct connection is suspected.
The skin, as the largest organ in the body and the most important barrier against environmental influences, is particularly affected. For example, primary damage thereto is caused mainly by irradiation or injury. The resulting damage to tissue or cells triggers inter alia processes in which free radicals are produced and/or antioxidants are consumed or promoters of autoxidation are released. In this connection, it is possible, for example, for iron ions or haem to be released, HOCl-producing phagocytes to be activated, the arachidonic acid cascade to be started or also the respiratory chain to be interrupted, in which case reactive oxygen species or free radicals are then released to a greater extent. These could damage lipids in cell membranes, proteins (including intracellular fibrin, enzymes and the intercellular support protein collagen), polysaccharides (e.g. the gel-forming hyaturonic acid) and also the DNA in the cells of the dermis. If this damage is not adequately countered by endogenous processes, the skin ages prematurely. This mainly becomes apparent from a sagging and thus the formation of wrinkles. In addition, cells may go out of control and form tumours, such as, for example, malignant melanomas.
The best known autoxidation is that of lipids, in particular of unsaturated fatty acids, in which in particular the membranes of otherwise intact cells are damaged. The autoxidation proceeds via a free-radical chain mechanism which can be divided into the three steps initiation, propagation and termination (see text books of organic chemistry). The free-radical initiation and propagation are heavily promoted by heavy metal ions, in particular the iron and copper ions present in physiolocial systems.
However, the oxidation of fats or other biomolecules also plays an important role in product protection, for example of cosmetics, pharmaceuticals or foods. In this connection, similar reactions to those described above always take place, the formation of free radicals being initiated in particular by heating, heavy metal ions or UV-light.
It is thus desirable to find substances which, in physiological systems, assist the natural defence mechanisms against free radicals and reactive oxygen species or, as protective substances in cosmetics, pharmaceuticals or foods, protect their oxidation-sensitive constituents against autoxidation.
Antioxidants are defined as substances which, in small concentrations compared to the oxidizable substrate, significantly delay or entirely prevent oxidation. Many antioxidants also function as free-radical scavengers and/or as complexing agents for heavy metal ions.
Some natural and very important antioxidants or free-radical scavengers are the tocopheroles (vitamin E), L-ascorbic acid (vitamin C) and glutathione. In addition, ubiquinone, .beta.-carotene and bilirubin (degradation product of porphyrin derivatives) play a role as antioxidants in vivo (cf. C. -M. Andersson, A. Hallberg, T. Hogberg, "Advances in the Development of Pharmaceutical Antioxidants", in Adv. Drug Res., B. Testa, U. A. Meyer (Ed.), Academic Press, London, 1996, p. 65-180). In addition, the polybasic acids, such as, for example, citric acid and amino acids, which have a chelating effect and can thus mask metal ions can also be mentioned. Another antioxidant specific to the skin is melanin formed in melanocytes, a mostly brown-black polymer, which is formed by oxidation and polymerization from aromatic amino acids such as L-tyrosine (cf. M. R. Chedekel, Cosmetics & Toiletries 1996, 111(1), 71-74).
The most important non-natural antioxidants, which are used particularly in the food industry for stabilizing fats and oils, are 2- and 3-tert-butyl-4-methoxyphenol (1:9 mixture, butylated hydroxyanisole, BHA) and 2,6-di-tert-butyl-4-methylphenol (butylated hydroxytoluene, BHT), propyl gallate (PG), dodecanyl gallate (DG) and 2-tert-butyl-1,4-dihydroxybenzene (TBHQ). Many of the products formed primarily from free-radical recombinations of phenoxy radicals are themselves also antioxidants. This is one reason why the antioxidants are frequently used as mixtures, since they display a mutual synergistic effect. However, some of these synthetic antioxidants have been classified as unsafe from a toxicological viewpoint (cf. S. M. Barlow, "Toxicological Aspects of Antioxidants Used as Food Additives", in Food Antioxidants, B. J. F. Hudson (Ed.), Elsevier, London, 1990, p. 253-307).
Antioxidants which are naturally occurring, particularly in plants, also include, for example, the .omega.-phenylalkyl acid derivatives, such as p-coumaric acid, caffeic acid, ferulic acid, sinapic acid and analogues and also some flavonoids.
Some ferulic acid amides of hydroxy-substituted 2-(phenyl-)-ethylamines (Martin-Tanguy, J.; Cabanne, F.; Pedrizet, E.; Martin, C., Phytochemistry 1978, 17 (11), 1927-1928) can also be found in nature; of these compounds, N-2-(4-hydroxyphenyl)ethyl-4-hydroxy-3-methoxy-E-cinnamamide, in particular, have been found in a large number of plants, such as, for example, in the tomato. The compound has also been isolated from black pepper, and the antioxidative effect has been described (JP 57,146,563; Nakatani, N.; Inatani, R.; Ohta, H.; Nishioka, A., EHP, Envir. Health Perspect. 1986, 67, 135-142). However, the compound is only present in small amounts in the plants (0.03%) and is not available in adequate amounts. In addition, as we have been able to establish, its action is no better than .alpha.-tocopherol (cf. Experiments 2 and 2).
A few other ferulic acid amides and caffeic acid amides of phenethylamines have been isolated from a variety of plants such as, for example, N-2-(4-hydroxyphenyl)ethyl-3,4-dihydroxy-E-cinnamamide from horse chestnuts (Martin-Tanguy, J.; Cabanne, F.; Pedrizet, E.; Martin, C., Phytochemistry 1978, 17 (11), 1927-1928) or from Annona crassiflora Mart. (Santos, L. P.; Boaventura, M. A. D.; de Oliveira, A. B.; Cassady, J. M., Planta Medica 1996, 62 (1), 76-77). In the case of some plants, particularly in the case of Solanaceae, they are formed as a response to an injury (example: N-2-(4-hydroxyphenyl)-2-hydroxyethyl-4-hydroxy-3-methoxy-E-cinnamamide in the potato: Negrel, J.; Pollet, B.; Lapierre, C., Phytochernistry 1996, 43 (6), 1195-1199).
The action of some N-hydroxycinnamoylhydroxyanthranilic acids, which are present inter alia in oats, as insecticides is described, for example, in NL 92,02,078.
Some polyhydroxylated dihydrocinnamamides of 2-(phenyl)ethylamines have been described in the literature, for example N-2-(3,4-dihydroxyphenyl)ethyl-3-(3,4-dihy-droxyphenyl)propanamide as an HIV-integrase inhibitor (Burke, T. R.; Fresen, M. R.; Mazumder, A.; Wang, J.; Carothers, A. M.; Grunberger, D.; Driscol, J.; Kohn, K.; Pommier, Y., J. Med. Chem., 1995, 38 (21), 4171-4178).
N-(4-hydroxy-3-methoxybenzyl)-4-hydroxy-3-methoxyphenylacetamide and its N-methyl derivative have been described as antiallergic active ingredients (WO 92 20,645).
At least the abovementioned phenolic acid amides occurring in nature have hitherto only been isolated or synthesized in small amounts and are thus available only in insufficient quantities.
The literature has not yet described any generally applicable and satisfactory processes for the synthesis of the aforementioned compounds. The classical coupling of the acid chlorides with amines frequently fails because of secondary reactions, in particular self-condensation of the phenolic acids, which cannot be completely suppressed even by using O-acetyl protective groups, and gives low yields (&lt;35%, cf. Tseng, C .F.; Iwakami, S.; Mikajiri, A.; Shibuya, M.; Hanaoka, F.; Ebizuka, Y.; Padmawinata, K.; Sankawa, U., Chem. Pharm. Bull. 1992, 40, 396-400).
A synthesis of some ferulic acid and caffeic acid tyramides by aminolysis of the N-hydroxysuccinimidyl ester for analytical purposes has been described in the literature (cf. Muhlenbeck, U.; Kortenbusch, A.; Barz, W., Phytochemistry 1996, 42,1573-1579). However, no details of yields were given.